SUMMARY Centenarians, people that live to 100 years of age, are remarkably protected from dementias, despite their advanced age. Understanding factors that protect centenarians from Alzheimer's disease (AD) may provide new leads for successful treatment. Our parent grant application investigates the role of SIRT6 protein in genome maintenance including DNA repair and suppression of LINE1 (L1) transposable elements. We discovered that L1s are activated during aging, especially in the brain, and the cytoplasmic DNA copies of L1s trigger type I interferon response. We hypothesize that the neuroinflammation induced by L1 activity contributes to the development of AD. The goal of Project 3 of the parent program project grant, is focused on the protein SIRT6 role in repressing L1 activity. SIRT6 deficient mice show neurodegeneration, and SIRT6 levels are reduced in patients with AD. Recently, our collaborator Yousin Suh (Albert Einstein), has identified via GWAS coding variants of SIRT6 that are only found in centenarians. Our preliminary data suggest that the centenarian variant of SIRT6 has higher enzymatic activity. Our hypothesis is that centenarian SIRT6 variant is a more powerful repressor of L1 activity leading to reduction of neuroinflammation and protection from AD. Here we propose to test whether centenarian SIRT6 variant has higher activity in silencing L1 elements and then examine whether overexpressing WT or centenarian SIRT6 variants in the brains of AD model mice delays the disease progression. These experiments will serve as a proof of principle that SIRT6 activators may be used as therapeutic target for AD and that small molecule activator compounds developed for SIRT6 can be used in AD treatment.